Immunogenicity of somatic mutations in human gastrointestinal cancers

TLDR

The immune response to somatic mutations in common epithelial cancers is poorly understood. We used next‑generation sequencing and high‑throughput immunologic screening to show that TILs from 9 of 10 metastatic gastrointestinal cancer patients recognize 1–3 neo‑epitopes derived from their own tumor mutations. No shared immunogenic epitopes were found, but a KRAS(G12D)-restricted TCR was identified, indicating that many gastrointestinal cancer patients harbor unique immunogenic mutations suitable for personalized immunotherapy.

Abstract

It is unknown whether the human immune system frequently mounts a T cell response against mutations expressed by common epithelial cancers. Using a next-generation sequencing approach combined with high-throughput immunologic screening, we demonstrated that tumor-infiltrating lymphocytes (TILs) from 9 out of 10 patients with metastatic gastrointestinal cancers contained CD4(+) and/or CD8(+) T cells that recognized one to three neo-epitopes derived from somatic mutations expressed by the patient's own tumor. There were no immunogenic epitopes shared between these patients. However, we identified in one patient a human leukocyte antigen-C*08:02-restricted T cell receptor from CD8(+) TILs that targeted the KRAS(G12D) hotspot driver mutation found in many human cancers. Thus, a high frequency of patients with common gastrointestinal cancers harbor immunogenic mutations that can potentially be exploited for the development of highly personalized immunotherapies.